The pyrrolizidine alkaloid, monocrotaline (MCT), produces lung injury accompanied by pulmonary hypertension and right heart hypertrophy. A reactive pyrrole metabolite of MCT produced in the liver is thought to be the proximate toxicant, but the mechanism by which the damage occurs is unknown. The most striking changes in pulmonary morphology in MCT intoxication include alterations in vascular endothelium and formation of thrombi containing large numbers of platelets. MCT-induced injury to pulmonary endothelium is associated with diminished capacity of the lung to inactive circulating 5-hydroxytryptamine (T-HT) and perhaps other agents which are stimulators of platelet aggregation. This study will examine the role of platelets in the etiology of lung injury produced by MCT. First, experiments will be performed to test whether MCT treatment of rats results in altered platelet function. Changes in platelet count, in adenosine diphosphate-or arachidonate-stimulated aggregation, in potentiation of aggregation by 5-HT, in platelet adhesiveness and in the ability of platelets to sequester 5 HT will be examined in MCT-treated rats. Preliminary results indicate that MCT administration decreases the number of circulating platelets. Effects on platelet function of exposure of platelets to MCT metabolites produced in vitro will also be examined. Next, effects of thrombocytopenia on the ability of MCT to cause lung injury will be tested. In adddtion, using a perfused rat lung preparation, the capacity of MCT-damaged platelets to injure lung will be evaluated. The possibility that injured pulmonary endothelium enhances aggregation of platelets and thereby worsens MCT-induced pulmonary injury will also be examined. For example, impaired removal by lung of circulating stimulators of platelets may lead to inappropriate platelet responses and further lung injury. To test this, experiments will be performed to determine if normal platelets have an altered tendency to aggregate in lungs from MCT treated animals. Finally, the requirement for platelets in lung toxicity resulting from MCT metabolites will be examined using isolated rat lungs. These studies will elucidate the role of the platelet in the response of the lung to toxic agents and may increase our understanding of how certain types of pulmonary hypertension develop.